Factors Affecting Anxiety and Depression in Women Undergoing Infertility Treatment: A Single-Center Experience

Abstract

Background: Infertility is a growing global public health concern associated with reduced quality of life and increased anxiety and depressive symptoms across diverse populations. However, factors influencing mental health in women undergoing infertility treatment remain insufficiently understood. This study aimed to assess psychological distress and identify factors associated with anxiety and depression in women receiving infertility treatment. Methods: A cross-sectional study was conducted at a leading regional infertility referral center. Women with confirmed infertility were consecutively recruited during routine visits. Psychological distress was assessed using the validated Patient Health Questionnaire-4. Demographic, reproductive, and clinical data were collected from self-report and medical records. Associations of infertility duration and age with comorbidities and other demographic variables were evaluated using appropriate parametric and nonparametric tests, and correlations were examined using Spearman’s rank coefficient. Results: The mean age was 34.9 ± 5.9 years and the median duration of infertility was 3 years. Nearly half of participants had mild psychological distress (49.3%), while 16.7% and 2.7% had moderate and severe distress, respectively; 32% screened positive for anxiety and 17.3% for depression. Longer infertility duration was significantly associated with higher depressive symptom scores, whereas other demographic and clinical variables showed no significant associations. Conclusions: Psychological distress is highly prevalent among women with infertility, with depressive symptoms increasing with longer infertility duration. These findings highlight the need for routine psychological screening and integration of mental health support into infertility care in clinical practice and long-term treatment planning, emphasizing a comprehensive, patient-centered approach to reproductive medicine.

1. Introduction

Infertility is an increasingly important global public health concern with substantial medical, psychological, and social implications. The World Health Organization estimates that approximately one in six individuals experiences infertility during their lifetime [1]. Between 1990 and 2021, the global prevalence of female infertility increased by more than 80%, accompanied by substantial increases in age-standardized prevalence and disability-adjusted life years (DALYs) [2,3]. While the greatest burden remains among women aged 35–39 years, prevalence is rising most rapidly in those aged 30–34 years, suggesting a shift toward earlier reproductive risk exposure and delayed childbearing patterns. Forecast models further indicate that the global burden of infertility is expected to continue rising in the coming decades [2,3], reinforcing the need for a broader understanding of its medical and psychosocial consequences.

Beyond its biological dimension, infertility is now recognized as a multidimensional condition strongly associated with psychological distress and reduced quality of life (QoL). A review of the global literature published in the last 10 years showed that across different cultures and countries, infertility adversely affects QoL, manifesting as depressive and anxiety symptoms as well as sexual dysfunction [4]. Infertility has been linked to increased psychological difficulties in both men and women following treatment failure [5]. However, a meta-analysis comparing stress, depression, anxiety and QoL found that these disturbances are more pronounced in women than in men [6]. In addition, a meta-analysis comprising 32 studies found that infertile women exhibited a higher prevalence of depression compared with the general population within the same country [7].

The psychological impact of infertility is also influenced by its underlying etiology. Ovulatory dysfunction and anovulation, tubal disorders, endometriosis, and uterine or cervical factors are the most common causes of female infertility [8] and may carry independent psychological consequences [9]. This is supported by significant population-based evidence, including a Danish cohort study of more than 2 million women, which demonstrated that reproductive system disorders are associated with an increased risk of depression, particularly within the first year following diagnosis [9]. However, findings across specific conditions remain inconsistent. For example, a nationwide Danish study of infertile women recruited from fertility clinics found no significant association between polycystic ovary syndrome (PCOS) and symptoms of anxiety or depression [10], suggesting that the psychological burden may vary depending on clinical context and patient selection. Similarly, while endometriosis has been associated with poorer QoL and increased depressive symptoms compared with infertility alone, anxiety levels appear to be less consistently affected [11].

In addition to clinical factors, sociodemographic and psychosocial variables also contribute to the heterogeneity of mental health outcomes among infertile women. Older age, lower educational level, longer duration of infertility, and reduced self-esteem have all been identified as potential risk factors for increased depressive symptoms [12,13]. However, these associations are not uniform across studies, and the relative contribution of clinical versus psychosocial determinants remains insufficiently clarified.

Despite the growing body of evidence linking infertility to psychological distress, there remains variability in findings across populations and settings, and limited consensus regarding the most important predictors of anxiety and depression in infertile women. Therefore, further research is needed to better characterize the burden of psychological distress in this population and identify key associated factors that may inform targeted screening and intervention strategies. The aim of this study was to investigate psychological distress in women undergoing infertility treatment and identify potential factors associated with anxiety and depression.

2. Materials and Methods

2.1. Procedure

This was an observational cross-sectional study conducted over a 6-month period at the Clinic for Gynecology and Obstetrics “Narodni Front,” University Clinical Centre of Serbia, a tertiary referral center for reproductive medicine and the main regional referral center for infertility care. Participants were consecutively recruited during routine clinical visits.

All participants completed the Patient Health Questionnaire-4 (PHQ-4), a validated screening instrument for the assessment of anxiety and depressive symptoms. Demographic, reproductive, and clinical data were obtained from patient self-reports and medical records.

The primary outcomes were PHQ-2, GAD-2, and PHQ-4 total scores, analyzed as continuous variables. Higher scores indicated greater symptom burden.

The study was conducted in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice (GCP). All participants provided informed consent prior to inclusion in the study. The study protocol was approved by the appropriate institutional ethics committee (Ethical Code: 25/VII-10).

2.2. Participants

The study included women with a confirmed diagnosis of infertility. Collected variables included age, duration of infertility, history of at least one birth, history of at least one miscarriage, Papanicolaou (PAP) test category, menstrual cycle regularity, and educational attainment.

Information on prior diagnostic and assisted reproductive procedures was recorded, including intrauterine insemination, in vitro fertilization (IVF), hysterosalpingography (HSG), and hysteroscopy.

The presence of medical and gynecological comorbidities was systematically assessed, including insulin resistance, PCOS, Hashimoto’s thyroiditis, endometrial polyps, uterine fibroids, endometriosis, ovarian cysts, tubal occlusion, and chronic medical diseases. Additionally, the presence of genital infections (Ureaplasma, Mycoplasma, and Chlamydia trachomatis) was recorded based on available clinical documentation.

2.3. Instrument

Psychological distress was assessed using the PHQ-4, a brief, validated screening instrument derived from the Patient Health Questionnaire-9 (PHQ-9) and the Generalized Anxiety Disorder-7 (GAD-7). The PHQ-4 consists of four items, including two items assessing anxiety symptoms (Generalized Anxiety Disorder-2 [GAD-2]) and two items assessing depressive symptoms (Patient Health Questionnaire-2 [PHQ-2]). The term “two items” refers to two specific questions for each domain; for example, anxiety is assessed with items such as “Feeling nervous, anxious or on edge,” while depression is assessed with items such as “Little interest or pleasure in doing things.”

Each item is rated on a 4-point Likert scale ranging from 0 (“not at all”) to 3 (“nearly every day”) over the preceding two weeks. Subscale scores for anxiety and depression range from 0 to 6, while the total PHQ-4 score ranges from 0 to 12, with higher scores indicating greater psychological distress. Total scores are categorized as normal (0–2), mild (3–5), moderate (6–8), and severe (9–12) psychological distress. A score ≥3 on the first two items (GAD-2) suggests clinically relevant anxiety symptoms, while a score ≥3 on the last two items (PHQ-2) indicates clinically relevant depressive symptoms.

The PHQ-4 has been widely validated in general and clinical populations, demonstrating good internal consistency and construct validity as a brief screening tool for anxiety and depressive disorders [14].

2.4. Data Analysis

Continuous variables were assessed for normality and summarized using means and standard deviations or medians (25th–75th percentile), as appropriate. Categorical variables were summarized as frequencies and percentages. Associations between psychological outcomes and clinical variables were evaluated using nonparametric tests, including the Mann–Whitney U test for comparisons between two groups and the Kruskal–Wallis test for comparisons involving more than two groups. Spearman’s rank correlation coefficient was used to assess relationships between continuous or ordinal variables. Associations of infertility duration and age with comorbidities and other demographic variables were assessed using the Mann–Whitney U or independent-samples t-test for two-group comparisons and Kruskal–Wallis or one-way ANOVA for comparisons across more than two groups. Statistical significance was defined as a two-sided p value < 0.05. Statistical analyses were performed using SPSS Statistics software, Version 27.0 (IBM Corp., Armonk, NY, USA).

3. Results

3.1. Population Characteristics

The mean age of the study population was 34.9 ± 5.9 years and the median duration of infertility was 3 years (2–4). Over half of the study population (54.7%) had a university degree.

Regarding reproductive history, the majority of participants had never given birth (88.7%) and 20% had experienced at least one miscarriage. Only 7.3% of women had undergone IVF, while HSG and hysteroscopy had been performed in 36% and 23.3% of women, respectively. Intrauterine insemination had been performed in 14% of participants. Most participants had regular menstrual cycles (82.7%), PAP category II (96%), and no chronic medical conditions (84%). Thrombophilia was present in 4.7% of women. Genital infections were rare: Mycoplasma was detected in 1.3% of women, Ureaplasma in 4%, and Chlamydia in none.

Metabolic and endocrine comorbidities included insulin resistance (24.7%) and polycystic ovary syndrome (PCOS) (18.7%), while Hashimoto’s thyroiditis was present in 18% of participants. Gynecological conditions were less common, with endometrial polyps in 15.3%, uterine fibroids in 11.3%, endometriosis in 10.7%, ovarian cysts in 10.7%, and tubal occlusion in 6.7% of women. Characteristics of the study population are shown in detail in

Table 1. Characteristics of the study population.

Sociodemographic Characteristics:
Age, mean ± SD	34.91 ± 5.874
Infertility duration, median (Q1–Q3)	3 (2–4)
Educational attainment, n (%)
University degree	82 (54.7)
Post-secondary	33 (22)
Secondary/High school	28 (18.7)
Primary school	7 (4.7)
Reproductive history:
At least one birth, n (%)
Yes	17 (11.3)
No	133 (88.7)
At least one miscarriage, n (%)
Yes	30 (20)
No	120 (80)
Gynecological procedures/treatments:
IVF treatment, n (%)
Yes	11 (7.3)
No	139 (92.7)
HSG, n (%)
Yes	54 (36)
No	96 (64)
Hysteroscopy, n (%)
Yes	35 (23.3)
No	115 (76.7)
Intrauterine insemination, n (%)
Yes	21 (14)
No	129 (86)
Gynecological/clinical characteristics:
Regular menstrual cycle, n (%)
Yes	124 (82.7)
No	26 (17.3)
PAP category II, n (%)
Yes	144 (96)
No	6 (4)
Chronic medical conditions, n (%)
Thrombophilia	7 (4.7)
No chronic medical conditions	126 (84)
Other	16 (10.7)
Genital infections:
Mycoplasma, n (%)
Yes	2 (1.3)
No	148 (98.7)
Ureaplasma, n (%)
Yes	6 (4)
No	144 (96)
Chlamydia, n (%)
Yes	0 (0)
No	149 (100)
Metabolic and endocrine comorbidities:
Insulin resistance, n (%)
Yes	37 (24.7)
No	113 (75.3)
PCOS, n (%)
Yes	28 (18.1)
No	122 (81.9)
Hashimoto’s thyroiditis, n (%)
Yes	27 (18)
No	122 (81.3)
Other gynecological conditions:
Endometrial polyps, n (%)
Yes	23 (15.3)
No	127 (84.7)
Uterine fibroids, n (%)
Yes	17 (11.4)
No	132 (88.6)
Endometriosis, n (%)
Yes	16 (10.7)
No	134 (89.3)
Ovarian cysts, n (%)
Yes	16 (10.7)
No	134 (89.3)
Tubal occlusion, n (%)
Yes	10 (6.7)
No	140 (93.3)

.

3.2. PHQ-4 Scores

Based on the PHQ-4 total score, nearly half of the participants (49.3%) exhibited mild psychological distress, while 16.7% and 2.7% had moderate and severe distress, respectively. Analysis of the subscales indicated that 32% of women had probable anxiety (GAD-2 ≥ 3) and 17.3% had probable depression (PHQ-2 ≥ 3) (Figure 1). The PHQ-4 demonstrated acceptable internal consistency in this sample (Cronbach’s α = 0.764), consistent with previous validation studies.

3.3. Primary and Secondary Outcomes

Univariate analyses demonstrated a weak but statistically significant, positive association between infertility duration and PHQ-2 scores (Spearman’s ρ = 0.187), indicating that women with a longer duration of infertility reported more depressive symptoms (

Table 2. Association of infertility duration and age with PHQ-4 and its subscales.

	Spearman’s Correlation Coefficient		p-Value
	Age	Infertility Duration	Age	Infertility Duration
Total Score	−0.097	0.146	0.236	0.074
GAD-2	−0.100	0.073	0.223	0.375
PHQ-2	−0.076	0.187	0.352	0.022

) (Figure S1). PHQ-2 scores correlated strongly with GAD-2 (ρ = 0.546) and PHQ-4 total scores (ρ = 0.856), reflecting the interrelated nature of anxiety and depressive symptoms. No other clinical or demographic variables were significantly associated with depressive or anxiety symptoms (Table S1).

There were several statistically significant differences between subgroups of women. Women with PCOS were younger than those without PCOS (32.9 ± 5.8 vs. 35.4 ± 5.8 years; p = 0.040). In contrast, women with uterine fibroids were older than those without fibroids (39.5 ± 4.1 vs. 34.3 ± 5.8 years; p < 0.001). Women with Ureaplasma infection were younger than those without the infection (28.2 ± 7.3 vs. 35.2 ± 5.7 years; p = 0.004). Women who had undergone hysteroscopy had a longer duration of infertility compared to those who had not (3 (2–5) vs. 2 (2–3) years; p = 0.004) (

Table 3. Differences between subgroups of women.

	Age, Mean ± SD	p-Value	Infertility Duration, Median (Q1–Q3)	p-Value
At least one pregnancy		0.498		0.284
Yes	34 ± 4.168		3 (2–4)
No	35.03 ± 6.060		3 (2–4)
At least one miscarriage		0.852		0.897
Yes	34.73 ± 6.705		3 (2–4)
No	34.96 ± 5.678		3 (2–4)
IVF treatment		0.167		0.065
Yes	37.27 ± 6.784		4 (2–6)
No	34.73 ± 5.783		3 (2–4)
HSG		0.211		0.139
Yes	34.11 ± 5.719		3 (2–5)
No	35.36 ± 5.942		3 (2–3)
Hysteroscopy		0.139		0.004
Yes	36.20 ± 5.754		3 (2–5)
No	34.52 ± 5.879		2 (2–3)
Intrauterine insemination		0.597		0.598
Yes	34.43 ± 4.166		2 (2–3)
No	34.99 ± 6.117		3 (2–4)
Regular menstrual cycle		0.765		0.584
Yes	34.99 ± 5.582		3 (2–4)
No	34.54 ± 7.223		2.5 (2–4)
PAP category II		0.167		0.696
Yes	34.78 ± 5.822		3 (2–4)
No	38.17 ± 6.765		2.5 (2–7)
Chronical medical conditions		0.712		0.322
Yes	35.41 ± 6.155		3 (2–4)
No	34.85 ± 5.881		3 (2–4)
Mycoplasma		0.345		0.418
Yes	31 ± 9.899		3.5 (3–4)
No	34.97 ± 5.84		3 (2–4)
Ureaplasma		0.004		0.387
Yes	28.17 ± 7.25		2 (2–3)
No	35.19 ± 5.668		3 (2–4)
Insulin resistance		0.083		0.349
Yes	33.46 ± 6.234		3 (2–5)
No	35.30 ± 5.7		3 (2–4)
PCOS		0.040		0.059
Yes	32.86 ± 5.765		3 (2–5)
No	35.39 ± 5.82		3 (2–4)
Hashimoto’s thyroiditis		0.875		0.693
Yes	34.78 ± 4.61		3 (2–3)
No	34.98 ± 6.148		3 (2–4)
Endometrial polyps		0.204		0.167
Yes	36.35 ± 5.773		3 (2–5)
No	34.65 ± 5.878		3 (2–4)
Uterine fibroids		<0.001		0.318
Yes	39.47 ± 4.064		3 (2–5)
No	34.25 ± 5.772		3 (2–4)
Endometriosis		0.332		0.828
Yes	33.56 ± 5.176		3 (1.5–4)
No	35.07 ± 5.949		3 (2–4)
Ovarian cysts		0.219		0.698
Yes	36.63 ± 6.417		3 (2–3.5)
No	34.71 ± 5.798		3 (2–4)
Tubal occlusion		0.162		0.712
Yes	32.4 ± 7.276		3 (2–4)
No	35.09 ± 5.751		3 (2–4)
Educational attainment		0.200		0.975
University degree	35.49 ± 5.5		3 (2–4)
Post-secondary	33.55 ± 6.078		3 (2–4)
Secondary/High school	34.14 ± 6.258		3 (2–3.5)
Primary school	37.71 ± 6.969		3 (2–3)

).

4. Discussion

In this cross-sectional study conducted at a tertiary referral center for reproductive medicine, we found a high prevalence of psychological distress among women with infertility, with nearly half of participants reporting mild distress and approximately one-fifth exhibiting moderate to severe symptoms. Anxiety symptoms were present in almost one-third of women, while depressive symptoms affected nearly one in five. These findings underscore the substantial psychological burden associated with infertility, even in a relatively young and medically stable population.

The most notable finding was the significant association between longer infertility duration and higher depressive symptom scores. These results align with prior studies showing that longer infertility duration is significantly associated with greater depressive symptom burden [13,14,15,16]. Furthermore, elevated cyclothymic, depressive, and anxiety symptoms have been independently associated with a 41–55% reduction in the odds of achieving a clinical pregnancy after adjustment for key clinical factors [17]. A randomised controlled trial by Soleimani et al. has demonstrated that structured stress management programs, such as infertility coach-led counseling, can significantly reduce perceived infertility-related stress and may enhance treatment outcomes, including oocyte count and pregnancy success [18]. Together, these findings underscore the importance of early identification and management of psychological distress as an integral component of comprehensive infertility care.

In contrast, no other demographic, reproductive, or clinical variables, including age, educational level, miscarriage history, menstrual regularity, or the presence of gynecological and endocrine comorbidities, were significantly associated with anxiety or depressive symptoms. However, other literature findings suggest that these factors indeed contribute to higher anxiety and depression [12,13,19]. In our cohort, prior exposure to diagnostic or assisted reproductive procedures, including IVF, was not associated with higher distress levels. Given the small proportion of women who had undergone IVF, this finding should be interpreted cautiously, but it may also indicate psychological adaptation or resilience among women who have already engaged with advanced fertility treatments. A study focusing on women undergoing IVF-embryo transfer found that 27% experienced depression and 18% experienced anxiety, with higher education and certain treatment timing or male-factor infertility reducing risk, while comorbidities and extended ART strategies were independently associated with increased risk [20]. Other factors, such as marriage status, BMI, smoking and alcohol use were also found to be associated with higher odds of psychological distress [21]. Although conditions such as PCOS and endometriosis have been linked to impaired mental health [9], we found no significant association with psychological outcomes. This may reflect relatively mild clinical presentations, effective management, or the predominance of infertility as the central stressor. Similar results were reported by Jannink et al. and Basirat et al., where PCOS was not associated with anxiety or depression [10,22]. However, other studies observed higher anxiety and depression in women with PCOS [23,24] and more depressive symptoms in those with endometriosis [11].

Depressive and anxiety symptoms often co-occur in women with infertility [25]. Consistent with this, strong correlations between depressive, anxiety, and total PHQ-4 scores in our cohort highlight the interrelated nature of these psychological responses. The PHQ-4 demonstrated acceptable internal consistency, supporting its reliability as a brief screening tool in reproductive medicine [14]. Its simplicity and ease of administration make it suitable for busy outpatient settings, facilitating early identification of women who may benefit from psychological assessment or intervention.

Clinically, infertility duration emerges as a simple, readily available marker to identify women at higher risk of depressive symptoms, aligning with prior evidence [13,14,15,16]. However, the lack of associations with most clinical and demographic variables suggests that targeted screening alone may be insufficient. While reproductive specialists recognize the negative impact of psychological distress, routine screening for anxiety and depression remains uncommon, underscoring the need for a systematic approach [26]. Consensus guidelines recommend integrated psychosocial assessment across the infertility care continuum to address emotional needs at all treatment stages, and psychological interventions have been shown to improve anxiety, depression, and overall well-being [27,28].

This study has several strengths, including consecutive patient recruitment, the use of a validated screening tool, and comprehensive assessment of reproductive and medical comorbidities. Nevertheless, certain limitations should be acknowledged. The cross-sectional design precludes causal inference, and longitudinal studies are needed to clarify temporal relationships between infertility duration and psychological distress. The single-center setting may limit generalizability, and the relatively small number of women undergoing IVF restricted subgroup analyses. Several potential sources of bias and residual confounding, including variation in IVF cycle stage, nutritional status, physical activity, cortisol levels and other psychosocial or biological variables, could not be assessed in the present study. Additionally, the PHQ-4 is a screening instrument rather than a diagnostic tool, and clinical interviews would be required to confirm psychiatric diagnoses.

5. Conclusions

In conclusion, psychological distress is highly prevalent among women with infertility, with depressive symptoms increasing with longer infertility duration. These findings emphasize the importance of routine psychological screening and the integration of mental health support into infertility care pathways. Addressing the psychological dimensions of infertility should be considered an essential component of comprehensive, patient-centered reproductive medicine.